Pierre Charles1, Élodie Perrodeau2, Maxime Samson3, Bernard Bonnotte3, Antoine Néel4, Christian Agard5, Antoine Huart6, Alexandre Karras7, François Lifermann8, Pascal Godmer9, Pascal Cohen10, Catherine Hanrotel-Saliou11, Nicolas Martin-Silva12, Grégory Pugnet6, François Maurier13, Jean Sibilia14, Pierre-Louis Carron15, Pierre Gobert16, Nadine Meaux-Ruault17, Thomas Le Gallou18, Stéphane Vinzio19, Jean-François Viallard20, Eric Hachulla21, Christine Vinter10, Xavier Puéchal10, Benjamin Terrier10, Philippe Ravaud2, Luc Mouthon10, Loïc Guillevin10. 1. Cochin Hospital, Paris Descartes University, and Institut Mutualiste Montsouris, Paris, France (P.C.). 2. Centre d'Epidémiologie Clinique, Hôpital Hôtel-Dieu, Université Paris Descartes, Sorbonne Paris Cité INSERM Unité 1153, Paris, France (É.P., P.R.). 3. Centre Hospitalier Universitaire de Dijon, INSERM, UMR 1098, University of Bourgogne Franche-Comté, FHU INCREASE, Dijon, France (M.S., B.B.). 4. CRTI UMR 1064, INSERM, Université de Nantes, and Centre Hospitalier Universitaire Nantes, Nantes, France (A.N.). 5. Centre Hospitalier Universitaire Nantes, Nantes, France (C.A.). 6. Centre Hospitalier Universitaire de Toulouse, Toulouse, France (A.H., G.P.). 7. Hôpital Européen Georges-Pompidou, Université Paris Descartes, Paris, France (A.K.). 8. Centre Hospitalier de Dax, Dax, France (F.L.). 9. Centre Hospitalier Bretagne Atlantique de Vannes, Vannes, France (P.G.). 10. Cochin Hospital, Paris Descartes University, Paris, France (P.C., C.V., X.P., B.T., L.M., L.G.). 11. Hôpital la Cavale Blanche, Centre Hospitalier Universitaire Brest, Brest, France (C.H.). 12. Centre Hospitalier Universitaire de Caen, Caen, France (N.M.). 13. Hôpitaux Privés de Metz, Metz, France (F.M.). 14. Hôpital de Hautepierre, Centre Hospitalier Universitaire de Strasbourg, Strasbourg, France (J.S.). 15. Centre Hospitalier Universitaire Grenoble Alpes, Grenoble, France (P.C.). 16. Clinique Rhône Durance, Avignon, France (P.G.). 17. Centre Hospitalier Universitaire Jean-Minjoz, Besançon, France (N.M.). 18. Centre Hospitalier Universitaire de Rennes, Rennes, France (T.L.). 19. Groupe Hospitalier Mutualiste de Grenoble, Grenoble, France (S.V.). 20. Centre Hospitalier Universitaire de Bordeaux, Pessac, France (J.V.). 21. Centre Hospitalier Universitaire de Lille, Lille, France (E.H.).
Abstract
BACKGROUND: Biannual rituximab infusions over 18 months effectively maintain remission after a "standard" remission induction regimen for patients with antineutrophil cytoplasmic antibody-associated vasculitis (AAV). OBJECTIVE: To evaluate the efficacy of prolonged rituximab therapy in preventing AAV relapses in patients with granulomatosis with polyangiitis (GPA) or microscopic polyangiitis (MPA) who have achieved complete remission after completing an 18-month maintenance regimen. DESIGN: Randomized controlled trial. (ClinicalTrials.gov: NCT02433522). SETTING: 39 clinical centers in France. PATIENTS: 68 patients with GPA and 29 withMPA who achieved complete remission after the first phase of maintenance therapy. INTERVENTION: Rituximab or placebo infusion every 6 months for 18 months (4 infusions). MEASUREMENTS: The primary end point was relapse-free survival at month 28. Relapse was defined as new or reappearing symptoms or worsening disease, with a Birmingham Vasculitis Activity Score greater than 0. RESULTS:From March 2015 to April 2016, 97 patients (mean age, 63.9 years; 35% women) were randomly assigned, 50 to the rituximab and 47 to the placebo group. Relapse-free survival estimates at month 28 were 96% (95% CI, 91% to 100%) and 74% (CI, 63% to 88%) in the rituximab and placebo groups, respectively, an absolute difference of 22% (CI, 9% to 36%) with a hazard ratio of 7.5 (CI, 1.67 to 33.7) (P = 0.008). Major relapse-free survival estimates at month 28 were 100% (CI, 93% to 100%) versus 87% (CI, 78% to 97%) (P = 0.009), respectively. At least 1 serious adverse event developed in 12 patients (24%) in the rituximab group (with 9 infectious serious adverse events occurring among 6 patients [12%]) versus 14 patients (30%) in the placebo group (with 6 infectious serious adverse events developing among 4 patients [9%]). No deaths occurred in either group. LIMITATION: Potential selection bias based on previous rituximab response and tolerance. CONCLUSION: Extended therapy with biannual rituximab infusions over 18 months was associated with a lower incidence of AAV relapse compared with standard maintenance therapy. PRIMARY FUNDING SOURCE: French Ministry of Health and Hoffmann-La Roche.
RCT Entities:
BACKGROUND: Biannual rituximab infusions over 18 months effectively maintain remission after a "standard" remission induction regimen for patients with antineutrophil cytoplasmic antibody-associated vasculitis (AAV). OBJECTIVE: To evaluate the efficacy of prolonged rituximab therapy in preventing AAV relapses in patients with granulomatosis with polyangiitis (GPA) or microscopic polyangiitis (MPA) who have achieved complete remission after completing an 18-month maintenance regimen. DESIGN: Randomized controlled trial. (ClinicalTrials.gov: NCT02433522). SETTING: 39 clinical centers in France. PATIENTS: 68 patients with GPA and 29 with MPA who achieved complete remission after the first phase of maintenance therapy. INTERVENTION: Rituximab or placebo infusion every 6 months for 18 months (4 infusions). MEASUREMENTS: The primary end point was relapse-free survival at month 28. Relapse was defined as new or reappearing symptoms or worsening disease, with a Birmingham Vasculitis Activity Score greater than 0. RESULTS: From March 2015 to April 2016, 97 patients (mean age, 63.9 years; 35% women) were randomly assigned, 50 to the rituximab and 47 to the placebo group. Relapse-free survival estimates at month 28 were 96% (95% CI, 91% to 100%) and 74% (CI, 63% to 88%) in the rituximab and placebo groups, respectively, an absolute difference of 22% (CI, 9% to 36%) with a hazard ratio of 7.5 (CI, 1.67 to 33.7) (P = 0.008). Major relapse-free survival estimates at month 28 were 100% (CI, 93% to 100%) versus 87% (CI, 78% to 97%) (P = 0.009), respectively. At least 1 serious adverse event developed in 12 patients (24%) in the rituximab group (with 9 infectious serious adverse events occurring among 6 patients [12%]) versus 14 patients (30%) in the placebo group (with 6 infectious serious adverse events developing among 4 patients [9%]). No deaths occurred in either group. LIMITATION: Potential selection bias based on previous rituximab response and tolerance. CONCLUSION: Extended therapy with biannual rituximab infusions over 18 months was associated with a lower incidence of AAV relapse compared with standard maintenance therapy. PRIMARY FUNDING SOURCE: French Ministry of Health and Hoffmann-La Roche.